I. Problem/Condition.

Basophilia is defined as an elevated absolute basophil count greater than 200 cells/uL or relative basophil count greater than 2%, though each laboratory should set their own normal ranges based on the local population. The elevation of these cells can often suggest underlying diseases, such as myeloproliferative disease or chronic inflammation. This article does not refer to basophilic staining, the purple "basic" dye that gives these white blood cells (WBCs) their name.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

There are three main categories when considering the cause of basophilia. First, hematologic causes include myeloproliferative diseases such as chronic myelogenous leukemia (CML), polycythemia vera, primary myelofibrosis (previously called myelofibrosis with myeloid metaplasia), and essential thrombocythemia. Systemic mastocytosis and hypereosinophilic syndrome are also considered myeloproliferative diseases and they too have been associated with basophilia. Other hematologic diseases that are associated with basophilia include other leukemias and myelodysplastic syndrome. Striking basophilia can be seen in the very rare chronic basophilic leukemia.

The second category involves chronic inflammation, a broad range of diseases that include tuberculosis, parasitic infections, inflammatory bowel disease, and rheumatoid arthritis. Although these diseases are chronic by nature, a persistent basophilia should not be ignored and hematologic neoplastic syndromes explored.

The third category is allergic including food and drug allergies and allergic rhinitis. The degree of basophilia may correlate with symptoms.

B. Describe a diagnostic approach/method to the patient with this problem

Conditions of chronic inflammation are often obvious, but the hematologic causes of basophilia can be subtle and therefore a low threshold for hematologic evaluation and consultation must be maintained for any patient with basophilia, particularly if there are other cell-line derangements.

1. Historical information important in the diagnosis of this problem.

Symptoms for the diverse causes of basophilia vary. Many are asymptomatic with the problem arising from routine blood work. Constitutional symptoms (fatigue, malaise, fever, etc.) are common in many of the abovementioned diseases. Infections are common in leukemias. Some specific symptoms are specific for myeloproliferative disease. For example, erythromelalgia is burning pain in the palms or soles of feet and aquagenic pruritus is itchy skin after water exposure such as a warm shower. However, frequently patients with myeloproliferative disease initially present with thrombosis- either arterial (myocardial infarction or stroke) or venous (deep vein thrombosis or pulmonary embolism).

Past records are extremely valuable to see the chronicity and trends of not only the basophils, but also other white blood cell (WBC) types, red blood cells (RBCs) and platelets. Although chronic inflammation can cause a leukocytosis, any leukocytosis with basophilia warrants consideration of a leukemia or other myeloproliferative disease. Acute increases (or decreases) in WBCs suggest acute leukemia, whereas slow increases over months or years suggest myeloproliferative disease.

Basophilia is associated with CML, but not chronic lymphocytic leukemia (CLL), so the WBC differential is very useful. In CML, the differential reflects a significant left shift, meaning an elevation of early or premature forms of WBCs not usually seen in peripheral blood - cells such as bands, metamyelocytes, myelocytes, and sometimes even blasts. This left shift will often go undetected by the automated cell counters that typically process cell counts. Therefore, a peripheral blood smear review is important.

If the red blood cell (RBC) count is elevated or rising, polycythemia vera should be placed high on the differential. However, remember that the elevation of RBC count (hemoglobin, hematocrit) can be suppressed by iron-deficiency. If the platelet count is elevated or rising over months to years, essential thrombocythemia must be considered. Thrombocytosis can also be reactive, a common finding in diseases of chronic inflammation and iron deficiency.

When associated with cytopenias, basophilia may underlie myelodysplastic syndrome.

Hypereosinophilic syndrome should be considered when eosinophilia >1500 cells/uL, constitutional symptoms and systemic manifestations (e.g. skin, pulmonary, etc.) are present. Systemic mastocytosis also causes constitutional symptoms and systemic manifestations and while eosinophilia can occur, it is not a prominent feature. Urticarial rashes and flushing are very common in systemic mastocytosis.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

The most important physical examination finding in regards to basophilia is the spleen. If splenomegaly is present, the likelihood of finding a myeloproliferative syndrome is very high. On examination, great care should be taken to have the patient relax the abdominal muscles, so that the examiner’s fingers can slip underneath the ribs (Traube's space) during inspiration. Although this procedure can be difficult and requires practice, the finding of a "mass" gliding under the fingertips is highly specific (92%) for splenomegaly. Of course, an ultrasound is much more sensitive than the physical examination, but perhaps less satisfying to the clinician.

Of note, occasionally in CML and primary myelofibrosis, splenomegaly can be massive. Therefore, one must not forget to start palpating for a spleen at the right lower quadrant of the abdomen and slowly migrate to the left upper quadrant so as not to miss the spleen's edge.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

As mentioned above, an ultrasound is useful for detecting splenomegaly especially in an overweight patient. However, a baseline ultrasound is also useful for therapeutic monitoring by accurately measuring spleen size changes.

An essential first step is examination of the peripheral blood smear. Key findings on the smear include a left-shift, defined as an increase in early or premature forms of WBCs in the peripheral blood. A left shift is highly suggestive of CML unless only one type of early form dominates the WBC differential, in which case acute leukemia must be considered and hematology consultation urgently sought.

Another crucial test (and easy to order) is Janus kinase 2 (JAK2) genotyping, an acquired genetic mutation that is found in 95% of patients with polycythemia vera, 50% of patients with primary myelofibrosis and 50% with essential thrombocythemia. More recently, calreticulin (CALR) has been found to be mutated in roughly one-third of patients with primary myelofibrosis and essential thrombocythemia, while mutations in the myeloproliferative leukemia (MPL) are found in 5% of cases. Gene sequencing panels have been developed using next generation sequencing techniques to obtain rapid genotyping of all three genes (and more) from peripheral blood or bone marrow and rapid diagnosis of myeloproliferative disease. A positive mutation solidifies the diagnosis of a myeloproliferative disease.

The other vital test for myeloproliferative disease is breakpoint cluster region-abelson (BCR/ABL) translocation, the Philadelphia chromosome, testing for CML. This finding is diagnostic for CML and can be done by three methods.

First, and least sensitive is cytogenetics (blood or bone marrow), where the white cells' chromosomes are stained and arranged by size. In CML, there is often a translocation of a segment of chromosome 9 (C-ABL) to chromosome 22's BCR gene - t(9;22). The other two highly sensitive methods are fluoresence in-situ hybridization (FISH) and polymerase chain reaction (PCR). PCR is the most sensitive. Testing for BCR/ABL should be ordered whenever the total WBC count is elevated in the setting of basophilia.

In mast cell diseases, tryptase is an appropriate screening test. Tryptase can also be elevated in hypereosinophilic syndrome, but its main feature is eosinophilia.

The ultimate diagnostic test is the bone marrow biopsy. This test is usually not necessary when diagnosing a myeloproliferative disease (except myelofibrosis), but it is essential in diagnosing myelodysplastic syndrome and sometimes acute leukemia. Acute leukemia usually results in a rapidly rising peripheral WBC count, but occasionally the WBCs are unable to release into the periphery and become trapped in the bone marrow, leading to neutropenia. The rule of thumb should be if any cytopenia accompanies basophilia, a hematologic consultation for bone marrow biopsy is mandatory.

If allergy is the suspected cause, remove the likely offending agent and consider referral to an allergist for testing.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

N/A

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Peripheral blood flow cytometry is useful only if the above findings suggest acute leukemia. It is typically not helpful in most myeloproliferative diseases or myelodysplastic syndrome. The exception is idiopathic myelofibrosis when high levels of cluster of differentiation molecule 34 (CD34) and WBCs can be detected in peripheral blood.

III. Management while the Diagnostic Process is Proceeding

A. Management of Basophilia.

If CML or acute leukemia is suspected, start intravenous hydration promptly and check electrolytes, renal function, uric acid, and lactate dehydrogenase (LDH) in preparation for treating tumor lysis syndrome, which can occur spontaneously. Allopurinol can be started and renally dosed, while rasburicase can be given if the uric acid is markedly elevated and/or renal failure is already present.

CML can now be successfully treated for extended duration with tyrosine kinase inhibitors, the classic example being imatinib. Acute myelogenous leukemia is still treated with 7+3 (7 days of cytarabine (Ara-C) and 3 days of an anthracycline such as daunorubicin or idarubicin).

Polycythemia vera and essential thrombocythemia should be treated with aspirin 81 mg daily to prevent thrombosis and cytoreductive therapy with hydroxyurea if the risk of thrombosis is high. Ruxolitinib is a new JAK2 inhibitor that has been approved for myelofibrosis and hydroxyurea-failed polycythemia vera.

The treatment for chronic inflammation targets the underlying cause. Allergies are treated with antihistamines and steroids.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

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